This invention relates to the preparation of a radiopharmaceutical. In particular, this invention relates to a process for the preparation a radiolabelled haloaromatic, as well as intermediate precursor compounds used in the process.
A number of radiolabelled haloaromatic compounds have found application in nuclear medicine. For example, meta-iodobenzylguanidine (xe2x80x9cMIBGxe2x80x9d), when radiolabelled with the iodine atom, is used in nuclear medicine as either an imaging agent for diagnosis, or as a therapeutic agent for neural crest tumors such as neuroblastoma. When labelled with the shorter-lived iodine-123, [123I]MIBG provides diagnostic cardiac images as well as images of tumors. The longer-lived [131I]MIBG is used at much higher radiation and chemical doses for the treatment of tumors.
By far the most common method of producing either [123I]MIBG or [131I]MIBG is by a Cu+ catalyzed isotopic exchange process which commences with 1-2 mg of MIBG and the desired amount of radioiodide. Because isotopic exchange is an equilibrium process, the product obtained by this process necessarily contains a significant amount of carrier MIBG. Considerable effort1 has been placed towards developing a convenient procedure that proceeds in near quantitative radiochemical yields. However, this method has the drawback of producing [131I]MIBG of low specific activity resulting in chemical doses of 1-5 mg when therapeutic samples are prepared. Doses of this magnitude carry potential hypertensive side effects
Accordingly, routes to no-carrier-added [131I]MIBG have been developed which could reduce the chemical dose of MIBG by about a factor of 100. Precursors to no-carrier-added [131I]MIBG, such as 3-tributylstannylbenzylamine2, 3-trimethylsilylbenzylguanidine2, and 3-trimethylstannylguanidinium3, have not found widespread application. These compounds have a short shelf life, and must be stored in a freezer shielded from light.
U.S. Pat. No. 5,555,185 discloses a no-carrier-added process of radiolabelling MIBG by halodestannylation. However, the process is disadvantageous in that a number of impurities remain in solution with the radiolabelled MIBG. In particular, toxic tin by-products remain in solution and must be separated before the radiolabelled MIBG is ready for use.
Accordingly, there is a need for a process for no-carrier-added synthesis of radiolabelled haloaromatic compounds, which can be easily and practically separated from possibly toxic impurities.
It is an object of the invention to provide a process for no-carrier-added synthesis of radiolabelled haloaromatic compounds, where the impurities can be removed by simple filtration, thereby making the process suitable for xe2x80x9ckitxe2x80x9d formulation.
It is also an object of the invention to provide intermediate insoluble polymer precursors which have a long shelf life and can be stored at room temperature without special conditions, and to which the unlabelled compounds and side products are bound, thereby facilitating removal of these undesirable impurities by filtration.
According to a first aspect of the present invention, a process of preparing a radiolabelled haloaromatic compound (I) of the formula: 
is provided, wherein:
R2 is selected from an alkyl group, an aryl group, a hydrogen atom, a halogen atom, a substituted oxygen atom, a substituted nitrogen atom, a substituted sulfur atom, a carbonyl group, a cyano group, an amino group, and a guanidine group. *X is selected from any suitable radiohalide, and is preferably selected from formula: 
xe2x80x83wherein
R1 is an alkyl group, and is preferably a butyl group. R2 is as described above.
According to a third aspect of the invention, a process of preparing an intermediate insoluble polymer of the compound of formula: 
is provided. The process comprises reacting the compound of formula: 
with a 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine compound of the structural formula: 
According to a fourth aspect of the invention, a process is provided for preparing an intermediate insoluble polymer compound of formula: 
comprising the steps of:
(a) reacting a first insoluble polymer compound of formula: 
xe2x80x83with a 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine compound of the structural formula: 
xe2x80x83to produce the compound having the formula: 
(b) reacting a compound having the formula: 
xe2x80x83with toluene and NCNH2 to convert the ammonium group to a guanidinium group.
According to a fifth aspect of the invention, a process is provided for preparing a compound of the formula: 
comprising contacting a compound of the formula: 
with iodine in an organic solvent.
According to a sixth aspect of the invention, a process is provided for preparing a compound of the formula: 
wherein n is selected from 123, 125, and 131: the process comprising contacting a compound having the formula: 
with a solution of NanI and an oxidizing agent in the presence of a buffering agent; wherein n is as described above.
Further features of the invention will be described or will become apparent in the course of the following detailed description.